Co-crystals Of Pyrazinamide And Hydrochlorothiazide

Background and Objective: Formation of pharmaceutical co-crystal is aneffective method to improve oral bioavailability of poorly water soluble drugs.Design and synthesis of pharmaceuitical co-crystals has became a hot topic in thepharmaceutical industry and crystal engineering research area. The world’s leadingpharmaceutical companies are actively engaged in research and development ofpharmaceutical co-crystal in order to alter the undesired physicochemical propertiesof drug candidates. The design, screening, synthesis, characterization ofpharmaceutical co-crystals are important compartments in the co-crystallizaitonstudies. So far, however, the studies on pharmaceutical co-crystal are still in itsinfancy. In this thesis, co-crystals of pyrazinamide (PZA) and hydrochlorothiazide(HCT) were investigated systematically based on design approach and the resultedco-crystals were fully characterized.Methods: Based on the knowledge of pharmaceutical co-crystal, co-crystals ofPZA and HCT were designed and synthesized. All the co-crystals were thoroughlycharacterized by X-ray diffraction, FT-IR and thermal analysis. Furthermore, thedissolution rates of the co-crystals were also tested and compared with API. Themain works carried out in this thesis were listed below:1. Screening of PZA co-crystals based on design.2. Preparation of PZA co-crystals by reaction crystallization.3. Characterization of PZA co-crystals and determination of their intrinsicdissolution rates.4. Screening of HCT co-crystals based on design.5. Preparation of HCT co-crystals by reaction crystallization.6. Characterization of HCT co-crystals and determination of their intrinsicdissolution rates.Results:(1) PZA was co-crystalized with adipic, sebacic, trans-aconitic andcitric acids through reaction crystallization method (co-crystals1–4). Single crystals of1–4were obtained by evaporation.(2) A series of amides, aromatic nitrogen compounds and carboxylates wereselected to co-crystallize with HCT, and seven co-crystals of HCT withpyrazinamide, nicotinamide, nicotinic acid,4-aminobenzoic acid,4,4’-bipyridine,1,2-bis(4-pyridyl)ethane and trans-1,2-bis(4-pyridyl)ethylene were synthesized byreaction crystallization (co-crystals5–11). Single crystals of5–11were obtainedby evaporation.(3) Many reliable solid state characterization techniques, including singlecrystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD),thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) andFourier-transform infrared spectroscopy (FT-IR) were used to characterize theco-crystals.(4) The properties of the co-crystals were studied systematically. The intrinsicdissolution rates (IDRs) of the co-crystals1–11and APIs were determined. TheIDRs of PZA and its co-crystals (co-crystal1–4) were performed in hydrochloricacid medium (pH=1.2) at37°C. The results showed that dissolution rates ofco-crystal3and co-crystal4were as1.76and1.43times as that of PZA, respectively.As a drug–drug co-crystal5was performed in phosphate buffer (pH=2.0) at37°C,the results showed that the intrinsic dissolution rate of co-crystal5was as1.45timesas that of HCT.Conclusion: Pyrazinamide and hydrochlorothiazide were selected as modelcompounds for the pharmaceutical co-crystal. The design, screening, structuralanalysis, characterization, and physicochemical properties of the co-crystals werestudied systematically. Four co-crystals of PZA and seven co-crystals of HCT wereobtained. Co-crystals3and5have significantly improved intrinsic dissolution rateswhen compared with corresponding API. Both co-crystals are promising candidatesfor developing new solid-state modifications for PZA and HCT, respectively.